Microparticulate caspase-1 regulates Gasdermin-D and pulmonary vascular endothelial cell injury

Mitra, S; Exline, M; Habyarimana, F; Gavrilin, M; Baker, P; Masters, SL; Wewers, MD; Sarkar, A

Author(s): Mitra, S; Exline, M; Habyarimana, F; Gavrilin, M; Baker, P; Masters, SL; Wewers, MD; Sarkar, A;
Details: Publication Year 2018-01-24,Volume 59,Issue #1,Page 56-64
Journal Title: American Journal of Respiratory Cell and Molecular Biology
Publication Type: Journal Article
Abstract: RATIONALE: Lung endothelial cell apoptosis and injury occurs throughout all stages of acute lung injury (ALI/ARDS) and impacts disease progression. Caspases 1, 4 and 5 are essential for completion of the apoptotic program known as pyroptosis that also involves pro-inflammatory cytokines. OBJECTIVES: Because GSDM-D mediates pyroptotic death and is essential for pore formation, we hypothesized that it may direct caspase-1 encapsulated microparticle (MP) release and mediate endothelial cell death. METHODS AND RESULTS: Our current work provides evidence that GSDM-D is released by LPS stimulated THP1 monocytic cells where it is packaged into microparticles along with active caspase-1. Furthermore, only MP released from stimulated monocytic cells that contain both cleaved GSDM-D and active caspase-1 induce endothelial cell apoptosis. MPs pretreated with caspase-1 inhibitor, YVAD, or pan-caspase inhibitor, ZVAD, do not contain cleaved GSDM-D. MPs from caspase-1KO cells are also deficient in p30 active GSDM-D, further confirming that caspase-1 regulates GSDM-D function. Although control MPs contained cleaved GSDM-D without caspase-1, these fractions were unable to induce cell death, suggesting that encapsulation of both caspase-1 and GSDM-D is essential for cell death induction. Release of microparticulate active caspase-1 was abrogated in GSDM-KO cells, although cytosolic caspase-1 activation was not impaired. Lastly, higher levels of microparticulate GSDM-D was detected in septic ARDS patient plasma when compared to healthy donors. CONCLUSIONS: Taken together, these findings suggest that GSDM-D regulates the release of microparticulate active caspase-1 from monocytes essential for induction of cell death and thereby may play a critical role in sepsis-induced endothelial cell injury.
Publisher: American Thoracic Society
Research Division(s): Inflammation
PubMed ID: 29365280
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6039876/
Publisher's Version: https://doi.org/10.1165/rcmb.2017-0393OC
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-03-27 09:20:16

Last Modified: 2020-06-17 09:22:25